Porous silica material for use as a pharmaceutical or dietary active ingredient

ABSTRACT

A porous silica material for use as a pharmaceutical or dietary active ingredient having pores in the mesoscale range (2-50 nm), wherein the average pore size of the pores in the mesoscale range is in the range of 2 to 25 nm, and the pore size distribution (PSD) in the mesoscale range is such that at least 80% of the pores fall within the range of 2 to 25 nm.

TECHNICAL FIELD

The present invention relates to a means for body fat composition(adipose tissue) lowering as well as a composition enabling this.

Background of the Invention

Obesity and overweight is a major factor in the cause of high bloodcholesterol and it is estimated that in the United States, roughly300,000 deaths per year are directly related to obesity, and more than80% of these deaths are in patients with a BMI over 30. For patientswith a BMI over 40, life expectancy is reduced significantly (as much as20 years for men and five years for women). Obesity also increases therisk of developing a number of chronic diseases, including: insulinresistance, type II diabetes, high blood pressure, high cholesterol,stroke, heart attacks, sleep apnea, congestive heart failure,osteoarthritis and cancer. In particular High levels of cholesterol havebeen associated with cardiovascular diseases as well as atherosclerosis.

There is currently only one pharmaceutical treatment for obesity:Orlistat, which is Food and Drug Administration (FDA) approved. Orlistatworks by affecting the body's process of nutrient adsorption in thegastro intestinal (GI) tract, blocking fat digestion and loweringcaloric absorption by inhibiting pancreatic lipases. An over the countercompound based on dietary fibers (for example, fermentable fibers basedon pectin) has been additionally commercialized. Other compounds on theverge of approval are based on mechanisms of increased metabolism, orsuppression of appetite. Drugs based on combination treatments haverecently been suggested as suitable alternatives in improving theefficacy of pharmaceutical compounds based for weight loss. Howeverseveral of those have had to be removed from the market due to the linkwith heart valve damage, for example fenfluramine and dexfenfluramine.Another example, Sibutramine has been withdrawn from the market in theUnited States, the UK, the EU, Australia, Canada, Hong Kong andColombia. Sibutramine risks (non-life threatening myocardial infarctionand stroke) outweigh the benefits of its use against obesity.

According to the World Health Organization (WHO) an 8.7% of the totalburden of disease of the European Region can be addressed to high bloodcholesterol. [Hockley T et al. European Cholesterol Guidelines report2007] Furthermore, cholesterol reduction in patients with coronarydisease retards or reverses the progression of atherosclerotic disease.[Garber A M et al. Ann Intern Med, 124:518-531, 1996] Statins are themost widely used lipid lowering drug used for prevention of coronarydiseases in high risk patients although there are controversiesregarding their positive effects in preventing death and cardiovasculardiseases in low and moderate risk patients. [Tonelli M CMAJ183:1189-1202, 2011; Ward S, Health Technol Assess. 11:1-160, 2007]There are alternatives to statins in the form of fibrates and resins,some of them are applied in combination with statin based therapies. Ithas been highlighted that lipid lowering treatments only haveeffectiveness in 51% of patients, after dietary recommendations andincreased physical activity. [European Heart Journal, 22:554-572, 2001].Furthermore, due to the large number of patients qualifying for statinbased therapies, there is a large number of intolerant patients andpatients with discomforts such as muscle complaints. The latter is themajor symptom limiting the use of statins. [Marcini J et al. Canadian Jof Cardiology, 27:635-662, 2011]. Hence, there is a need of new and moreefficient lipid lowering treatment alternatives with and without thecombination of lipid lowering drugs.

Silicon occurs naturally in nature as silicon dioxide (SiO2) or thecorresponding silicic acids that result from the hydration of the oxide.Human serum contains 11-25 μg silicon/dL [EFSA Journal, 2009, 1132,1-24] and remains relatively constant suggesting that it is rapidlydistributed in the body and/or excreted. Absorbed silicon is mainlyexcreted via the urine without evidence of toxic accumulation in thebody. [EFSA Journal, 2009; Reffit D M et al. J Inorg Biochem,76:141-147, 1999] Hence, silicon content in the urine can be used asindicator for silicon absorption. [Reffit 1999, Jugdaohsingh R et al. AmJ Clin Nutr, 75:887-893, 2002] Jugdaohsingh et al. showed thatfood-based silica is digested and absorbed from the gastrointestinaltract in humans. A mean of 40.9% of the ingested silicon was excretedwithin 6 h after intake with some variations depending on the siliconsource, corresponding to 20 mg excreted silicon/day. [Jugdaohsingh 2002]The intake of silica has already been proposed for lowering blood lipidor cholesterol levels e.g. in the form of: (a) fumed silica, (b)diatomaceous earth and (c) silica hydrogel:

(a) Studies performed in rats by Peluso et al. have shown that intakehad a clear hypocholesterolemic effect on Cholesterol-Fed rats byreducing total levels of plasma cholesterol, with a decrease in bothvery-low density lipoprotein (VLDV), and low-density lipoprotein (LDL)cholesterol. [Peluso R M et al. J Nutr Met, 124:853-860, 1994] Theintake of silicon dioxide in (a) was in the form of non-porous fumedsilica (CAB-O-SIL® EH-5, typically with average size between 120 and 300nm, and typically with BET surface area of approximately 380 m²/g). Nochanges in body weight were observed when comparing control animals tothe animals receiving silicon dioxide. [Peluso R M et al. J Nutr Met,124:853-860, 1994](b) Wachter et al. showed a lowering effect on blood cholesterol levelsin humans after oral intake of diatomaceous earth. [Wachter H et al. EurJ Med Res, 3:211-215, 1998; EP 0778027 A2] Diatomaceous earth is alargely amorphous silica from sedimentary rock, used as dietary foodadditive for improving, e.g., the shape of nails, hairs and skin(approved by the U.S. FDA as food additive). Its intake reduced bloodcholesterol as well as LDL cholesterol and triglycerides. No changes ofbody mass were observed. [Wachter 1998](c) Large pore size silica hydrogel containing about 50 to 80 weight-%water can reduce lipid or cholesterol blood levels in chicken fed onhigh fat diet. [U.S. Pat. No. 4,180,566 A] The silica hydrogel has noeffect on body weight neither under standard nor high fat diet.

The blood lipid lowering effect in the above mentioned publications wasmajorly adjudicated to bile acid sequestration [as also described inU.S. Pat. No. 4,185,088 A] and elimination through the stools leading toincreased production of bile acids from cholesterol in the organism.Neither body fat nor body weight lowering effects are observed in theabove referred publications.

Recently, ordered porous materials (e.g. silica) have been studied ascarriers for the delivery of poorly water-soluble drugs and forcontrolled release of pharmaceutical compounds. [Salonen J, et al. JControl Release 108:362-374, 2005; Kaukonen A M, et al. Eur J PharmBiopharm 66:348-356, 2007; Shen S. C. International Publication NumberWO 2010/050897 A1, and Garcia-Bennett et al. ChemMedChem, 43-48, 2012].

Ordered mesoporous materials exhibit a 2-dimensional (2-d) or3-dimensional (3-d) ordered array of cylindrical or cage type pores (inthe range of 2 to 50 nm) separated by thin silica walls. Bioactive drugscan be molecularly dispersed in these pores up to a certain loading. Theinflux diffusion of water to the pore surfaces provides for a rapidrelease of poorly water-soluble drugs if the drug compound is loaded inan amorphous state.

Ordered mesoporous materials have been attracting much attention becauseof the regular and adjustable pore size, different pore structures, highsurface area and pore volume, high concentrations of silanol groupswhich ease their functionalization and conjugation to other chemicalentities. They are particularly useful for the selective adsorption ofdifferent molecules due to their precise pore size distribution, and assuch, are readily used in sensors and for specific adsorption of gases.Numerous syntheses have been reported for mesoporous materials based onthe use of templates, or porogens, for the formation of orderedporosity. The most common preparations use surfactants as the templates,allowing tailoring porosities in the orders between 1.5 and 30 nm withgood control over pore size distribution, pore structure and particlesize. Examples of these materials include MCM-41, AMS-6, and SBA-15.Nanoporous folic acid materials (NFM-1) have been developed by using thenon-surfactant folic acid as template. [Garcia-Bennett A E,International Publication Number WO 2009/101110 A2] These materials havethe 2-D hexagonal pore structure with the pore size controllable in therange between 1.8 and 3.5 nm and varied morphologies.

BRIEF SUMMARY OF THE INVENTION

It has now surprisingly been found that porous materials, in particularporous silica materials, having a certain content of porosity in themesoscale range (2-50 nm) have an unexpected effect in terms ofreduction of human or animal body fat composition.

Thus, the present invention relates to a means for body fat composition(adipose tissue) lowering as well as a composition enabling this.

In particular, the present invention relates to a weight loss andcholesterol lowering (hypocholesterolemic) active ingredient, foodadditive and formulation which is comprised of a porous material havinga defined content of porosity in the mesoscale range. The formulationmay be enhanced with the addition of other cholesterol or weight lossinducing pharmaceutical or neutraceutical compounds or administered onits own, and it is especially suited for oral administration.

According to the present invention, the mechanism of weight loss andcholesterol lowering is based on the adsorption of biomolecules (bileacids, lipids, proteins and enzymes) and water into the porous matrix ofthe active porous ingredient or formulation, which may be speciallydesigned for the selective adsorption of low-density lipoprotein LDL andother gastro-intestinal molecules. This leads to a depletion of theencapsulated gastro-intestinal molecule, for example lipases and relatedmolecules. The result of administration of the innovative activeingredient and formulation when specially designed is a decrease in bodyfat composition and subsequently also a decrease in weight, and alowering of cholesterol and other blood lipids.

Whilst other porous materials have been utilized for lowering ofsystemic cholesterol, this invention includes materials with narrow poresize ranges that show a significantly greater specificity towardslipases and related molecules, which leads to an effective lowering ofbody fat composition which in turn can result in a weight decreaseeffect with lower or no secondary effects compared to other existingweight decrease treatment alternatives.

In particular, the present invention relates to an oral dietary and/orpharmaceutical formulation comprising at least a porous silica material,which when administered orally as e.g. a pill, powder, suspension, as agel or in solution results in body fat composition (adipose tissue)lowering over time, with or without subsequent weight reduction.

The invention relates also to the preparation of an oral dietary and/orpharmaceutical formulation comprising at least a porous amorphous silicamaterial, which when administered as a pill, powder, suspension, as agel or in solution results in overtime weight reduction. The lowering ofbody fat composition may be accompanied with a lowering of bloodcholesterol levels and other biomolecules.

Whilst NFM-1 materials [Garcia-Bennett A E, WO 2009/101110 A2] areuseful for the present invention, a higher degree of body weight lossand cholesterol adsorption is found in materials with pore sizes in theorders between 3 and 100 nm. Thus, further improvements can additionallybe obtained by incorporating hierarchical porous structures; definedhere by having pores in several orders of magnitude, for examplemacropores (50 nm and above) in addition to mesopores (2 to 50 nm),within one porous matrix. Examples of such hierarchical materials withsilica and alumina compositions are well characterized by the work ofNakanishi et al. [Colloids and Surfaces A: Physicochemical andEngineering Aspects 187-1188:117-122, 2001]

Even if porous silica materials are preferred, the present inventiondoes not exclude the use of other porous material compositions, forexample amorphous alumina compositions, or porous silicon compositions,or amorphous porous carbon compositions, where the selective adsorptionof similar biomolecules may be also achieved.

It is worth noting that the present invention does not relate to the useof, e.g., diatomaceous earths (a naturally occurring compound), but to asynthetic porous material, preferably silica, with sharp pore sizedistributions in the meso-scale (i.e. between 2 and 50 nm). The presentinvention discloses that the use of lower pore sizes have a specificscavenging effect for cholesterol molecules, unlike the unspecificbinding observed with large pore diatomaceous earths.

Thus, in its more general definition, the present invention relates to aporous silica material for use as a pharmaceutical or dietary activeingredient having pores in the mesoscale range (2-50 nm), wherein theaverage pore size of the pores in the mesoscale range is in the range of2 to 25 nm, and the pore size distribution (PSD) in the mesoscale rangeis such that at least 80% of the pores fall within the range of 2 to 25nm.

Advantageously, the average pore size of the pores in the mesoscalerange is in the range of 7 to 15 nm, preferably 8 to 13 nm, morepreferably 10 to 12 nm.

Advantageously, at least 90%, more preferably at least 95% of the poresin the mesoscale range fall within the defined range of 2 to 25 nm.

Preferably the BET surface area is between 300 and 1300 m2/g.

Advantageously, the BET surface area is between 450 and 950 m2/g,preferably between 500 and 900 m2/g, more preferably between 550 and 850m2/g, more preferably 600 and 800 m2/g.

Preferably the pore volume measured by nitrogen adsorption is in therange of 0.3 to 1.7 cm3/g, preferably 0.7 to 1.6 cm3/g, more preferably0.8 to 1.5 cm3/g, more preferably 0.9 to 1.4 cm3/g.

In an embodiment of the porous silica material according to the presentinvention, the porous silica material additionally has a hierarchicalporous structure containing both pores in the mesoscale range andmacropores, where macropores are defined as pores larger than 50 nm.Thus, in addition to the mesopores, the porous materials of theinvention may include macropores (i.e. pores above 50 nm). Inparticular, the porous materials of the invention may contain ahierarchical porous structure as defined by pores in the range between 2nm and 50 nm and macropores in the size between 50 nm and 5 um.

The porous silica material of the invention is suitable for use inlowering of animal or human body fat composition.

Other possible uses of the porous silica material of the invention is inthe prophylaxis or treatment of: obesity or metabolic syndrome (asdefined by the International Diabetes Federation) or dyslipidemia orelevated blood pressure or hypertension or type 2 diabetes or insulinresistance or hyperglycemia.

Other possible uses of the porous silica material of the invention isfor lowering triglyceride or cholesterol including lowering ApoB orlowering non-HDL cholesterol or lowering LDL-c or raise HDL-c levels inthe blood.

A further use of the porous silica material of the invention is forlowering glucose levels in the blood.

A pharmaceutical composition comprising a porous silica material asdescribed in the present application as an active ingredient is alsopart of the present invention.

The pharmaceutical composition according to the invention mayadvantageously contain a further active pharmaceutical ingredient orcombination of ingredients.

The pharmaceutical composition according to the invention can be in theform of a pill, a powder or a suspension for oral administration.

As an example, said further active pharmaceutical ingredient orcombination of ingredients can be an ingredient or combination ofingredients with weight lowering properties.

In another embodiment of the invention the formulation may be an activepharmaceutical or dietary ingredient comprising solely of a poroussilica material, in which the silica composition does not exceed achloride concentration of 250 ppm, or a heavy metal concentration of 25ppm.

A food composition comprising a porous silica material as described inthe present application as an active ingredient is also part of thepresent invention.

The food composition according to the invention may advantageouslycomprise a liquid or solid flavorant.

In general, a porous material for use as a pharmaceutical or dietaryactive ingredient having pores in the mesoscale range (2-50 nm), whereinthe average pore size of the pores in the mesoscale range is in therange of 2 to 25 nm, and the pore size distribution (PSD) in themesoscale range is such that at least 80% of the pores fall within therange of 2 to 25 nm, is part of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Main Component of the Active Ingredient: Mesoporous Silica Material.

Mesoporous silica materials, which were invented in 1992 (Kresge et al.Nature 359:710-712, 1992), are synthetic materials with pores in themesoscale range (between 2 to 50 nm) and amorphous pore walls. They havelarge surface areas in the range of about 300 to 1500 m2/g (as measuredby nitrogen adsorption).

The present invention relates to the use of porous materials, inparticular porous silica materials, for lowering of animal or human bodyfat composition wherein the porous silica has narrow pore sizedistributions in the mesoscale range, the average pore size being about2 to 25 nm (as measured by nitrogen adsorption and calculated using theDensity Functional Theory) and BET (Brunauer-Emmett-Teller theory)surface areas between 300 and 1300 m²/g. Preferred ranges of surfacearea values are between 450 and 950 m²/g, or 500 and 900 m²/g, or 550and 850 m²/g, or 600 and 800 m²/g

In one embodiment the porous silica has a narrow pore size distributionin the mesoscale range of about 2 to 25 nm as measured by nitrogenadsorption and calculated using the Density Functional Theory.

Preferably, the porous silica has a narrow pore size distribution in themesoscale range of about 7 to 15 nm as measured by nitrogen adsorptionand calculated using the Density Functional Theory. More preferably, theporous silica has a narrow pore size distribution in the mesoscale rangeof about 8 to 13 nm as measured by nitrogen adsorption and calculatedusing the Density Functional Theory.

Even more preferably, the porous silica has a narrow pore sizedistribution in the mesoscale range of about 10 to 12 nm as measured bynitrogen adsorption and calculated using the Density Functional Theory.

For the purposes of the present invention, with the term narrow poresize distribution in the mesoscale range it is meant that at least 80%of the mesopores (i.e. of the pores in the range 2-50 nm) fall withinthe above-defined pore range.

Preferably at least 85% of the mesopores fall within the above-definedpore range; more preferably at least 90% of the mesopores fall withinthe above-defined pore range; even more preferably at least 95% of themesopores fall within the above-defined pore range.

The present invention differs from the publications and patents referredto in the background, by the sharp pore size distributions in themesoscale range which allows for higher adsorptive selectivity and awater content below 15% prior to preparation of the final formulation.The present invention does not include any washing with ammoniumhydroxide solution at any step of its preparation.

Mesoporous amorphous silica is here defined as a material not possessinglong range order in the atomic scale and capable of adsorbing a certainamount of nitrogen gas above a level of 50 cm³/g (as measured bynitrogen adsorption experiments). Amorphous silica materials adsorbingnitrogen below the aforementioned level and for the purpose of thisinvention are considered to be non-porous and are hence excluded fromthe present invention. Porous silica materials useful for the presentinvention may otherwise be referred to as colloidal silica but may alsobe known as: precipitated silicon dioxide, silica gel, hydrous silica,hydrated silicic acid, polysilicic acid gel and E551; generallydescribed under CAS Nos.: 7631-86-9 (Silica), 112945-52-5 (Silica,amorphous, fumed, crystalline-free) and 112926-00-8 (Silica gel andprecipitated silica, crystalline-free). The present invention excludesthe use of diatomaceous earths and zeolites, since the former showlittle specificity in the context of the present invention, and thelatter is not amorphous silica but a porous crystalline material. Inorder for silica to be useful in the present invention a pore sizelarger than 2 nm is necessary. An example of a porous silica compositionthat may be used in the present invention as an active ingredient or aspart of a formulation is included in Table 1. The method ofcharacterization is also included as defined by the Pharmacopeia.

TABLE 1 Test parameter Specification Method Result Characters,appearance White or almost Ph Eur 7.3 White, fine powder white, light,fine, January 2011: 0434 amorphous powder Identification To pass test PhEur 7.3 Passed test January 2011: 0434 pH 3.5-5.5    Ph Eur 7.3 4.24January 2011: 0434 Chlorides Max 250 ppm Ph Eur 7.3 <250 ppm January2011: 0434 Heavy metals Max 25 ppm Ph Eur 7.3  <25 ppm January 2011:0434 Loss on ignition Max 5% Ph Eur 7.3 2.25% January 2011: 0434 Assay99.0-100.5% Ph Eur 7.3 100.0% January 2011: 0434

A minimum particles size distribution of 300 nm (as measured by ScanningElectron Microscopy) is required for the best mode of use with respectto silica compositions used for the present invention. Particles belowthis size may lead to systemic adsorption of silica and cause increasedsilicon levels in blood. Particles above this size are not associatedwith systemic adsorption and are rapidly cleared from the GI tractthrough feces. The present invention does not identify a particularparticle shape or size, and several shapes with a variety of aspectratios from fibers to spheres are described in the examples.

Composition of the Formulation

The present invention refers to a formulation that may comprise theactive ingredient (silica) in several different compositions, namely(note that all concentrations below refer to weight percentages):

-   -   In one embodiment of the present invention the formulation        contains between 95% and 100% of porous amorphous silica (main        component of the present invention) acting as a pharmaceutical        active ingredient or dietary ingredient;    -   In another embodiment of the present invention the formulation        contains between 1% and 99% of a pharmaceutical active        ingredient or dietary ingredient composed of porous amorphous        silica (main component of the present invention), and between 1        to 99% of a secondary pharmaceutical active ingredient. Examples        of secondary pharmaceutical active ingredients and combinations        of these include those included in the following formulations,        or groups of compounds; Orlistat (Xenical), Lorcaserin,        Sibutramine (Reductil or Meridia), Rimonabant, Metformin,        Exenatide, Exenatide, Pramlintide (Symlin) a synthetic analogue        of the hormone Amylin, phenylpropanolamine and other        amphetamines.    -   In another embodiment of the present invention the formulation        contains between 5% and 99% of a pharmaceutical active        ingredient or dietary ingredient composed of porous amorphous        silica (main component of the present invention), and a        secondary active ingredient such as fat-soluble vitamins (A, D,        E and K), pro-vitamins, and commercially available stabilized        forms of fat-soluble vitamins, and water soluble vitamins in        concentrations between 1% and 95%.    -   In another embodiment of the present invention the formulation        may contain excipients. Excipients are components of a finished        drug product other than the active pharmaceutical ingredient and        are added during formulation for a specific purpose. Although        listed as inactive ingredients by FDA, excipients generally have        well-defined functions in a drug product.    -   In another embodiment of the present invention the formulation        may contain excipients such as: cellulose derivatives such as        Methyl cellulose, Ethyl cellulose, Hydroxyethyl cellulose,        Hydroxypropyl cellulose, Hydroxyethyl methylcellulose,        Hydroxypropyl methyl cellulose, Carboxymethyl cellulose etc;        vinyl polymers such as Polyvinyl alcohol, polyvinylpyrrolodone,        poly(vinylpyrrolidone-co-vinyl acetate) etc.; and ethylene        polymers like PEG. The invention may in addition contain as        further constituents conventional pharmaceutical auxiliary        substances such as suitable filler, binder, disintegrants,        lubricants, glidants, swellable erodible hydrophilic materials,        insoluble edible materials, taste-masking and odor-masking,        salts, sugars, sweeteners, plant extracts, surfactants. Examples        of surfactants include TPGS, Tween® 20, Crenophor® RH40 etc.        Similar to surfactants, cyclodextrins are well known for their        stabilizing capability and capacity.    -   In another embodiment, the present invention may be used        together with other pharmaceutical active compounds.

The porous materials of the present invention, when used together withsecondary active pharmaceutical compounds, can allow for lower effectivedoses of the second active component.

This can allow for lower secondary effects of the second activecomponent and hence also better patient compliance with respect to thesecond active component in the formulation.

The present invention can be evaluated when administered in combinationwith statins, orlistat or other active pharmaceutical ingredientstypically used by the target population, using obesity models such asC57BL/6J mice with diet induced obesity and hypertension.

Incorporation Methods of Pharmaceutical and Dietary Active Agents

In a certain embodiment of this application the active ingredient isused together with a separate active pharmaceutical ingredient capableof lowering cholesterol. In the case of co-administration the presentinvention is best administered as pill, tableted together with theadditional ingredient. Tableting technologies such as the formation ofpills, capsules, solutions, dispersions, emulsions, or others may beutilized. The use of these has no effect neither in the cholesterollowering properties, nor in the weight loss properties obtained so longas the administration is given orally. In another embodiment of theinvention the formulation may be used together with pharmaceuticalactive compounds which are employed to reduce blood cholesterol, andhave a boosting effect to their action.

In another embodiment of the invention the formulation may be usedtogether with naturally derived active compounds, including plant,fruit, or vegetable extracts, concentrates, fibers, roughage, which areemployed to reduce blood cholesterol, and have a boosting effect totheir action.

In another embodiment of the invention the formulation may be usedtogether with other porous materials including clays, husks, nutshells,seashells, CaCO₃, and other naturally occurring porous materials whichhave the ability to uptake water, fats, lipids and cholesterol.

Mechanism of Action

Mesoporous silica's large surface area may act similar to dietary fibersand adsorb lipids or bile acids within the gastrointestinal tract, hencereducing their absorption and re-sorption, respectively. Silica mayadsorb fatty acids, lipids, water, enzymes, proteins and bile acidsleading to their subsequent excretion and affecting the gastrointestinalconcentration of the aforementioned. In turn this may lead to anincrease of hepatic bile acid biosynthesis which results in a furtherlowering effect on blood cholesterol levels. Examples of lipids aremono-, di-, or tri-acylglycerols and related molecules. Examples of bileacids include; cholic acid, chenodeoxycholic acid, deoxycholic acid andrelated molecules biosynthesised from cholesterol [for further examplessee Maitra et al CURRENT SCIENCE, VOL. 87, NO. 12, 25 Dec. 2004]Examples of enzymes that may be adsorbed or inhibited include gastriclipases, pancreatic carboxyl ester hydrolaze and pancreaticlipase-related protein 2 which are major players in lipid and fatdigestion. The intake of mesoporous silica may also result inalterations in the end-products of bile acid bacterial metabolism,modulating either the synthesis of cholesterol or its catabolism to bileacids. The present invention excludes active ingredients that result insystemic adsorption or increases in silicon blood levels after oraladministrations.

The present invention leads to a lowering of body fat composition andbody weight after oral administration, which makes it different from thepublications and patents mentioned in the Background of the invention as(a), (b) and (c), where administration of silica leads to a lowering ofblood lipids (cholesterol) but not to any changes in body weight orcomposition. Also different from previous publications and patents, nochanges in blood levels of cholesterol, HDL or triglycerides areobserved after oral administration of the present invention for 12 weeks(see Example 4).

TABLES AND FIGURES

The present invention is not limited to the tables and figures listedbelow, but these are included in order to exemplify the presentinvention.

Table 1. Example of a porous silica composition that may be used in thepresent invention as an active ingredient or as part of a formulation.The method of characterization is also included as defined by thePharmacopeia.

Table 2. Examples of textural properties of porous silica materials thatmay be suitable for the present invention.

FIGS. 1, 2 and 3, Example 2A. The example is included to show the effectof a typical Silica 2 material (Table 2) on lowering of body fatcomposition and body weight.

FIG. 1. Scanning electron microscopy image (FIG. 1A) and pore sizedistribution (FIG. 1B) of a mesoporous silica material included in thepresent invention.

FIG. 2. Development of female mice body weight, body fat composition andlean during the study described in Example 2A. The figure shows asignificant effect of the silica particles with an average pore size ofabout 11 nm (FIG. 1) on lowering body fat composition and body weight.

FIG. 3. Development of male mice body weight, body fat composition andlean during the study described in Example 2A. The figure shows asignificant effect of the silica particles with an average pore size ofabout 11 nm (FIG. 1) on lowering body fat composition and body weight.

FIGS. 4, 5 and 6, Example 2B. The example is included to show that amaterial with structural properties typical for a Silica 1 (Table 2)material has a weaker effect than a typical Silica 2 (Table 2) materialon lowering body fat composition and body weight.

FIG. 4. Scanning electron microscopy image (FIG. 4A) and pore sizedistribution (FIG. 4B) of a mesoporous silica material included in thepresent invention.

FIG. 5. Development of female mice body weight, body fat composition andlean during the 20 weeks study described in Example 2B. The figure showsthe effect of the silica particles with an average pore size of about 3nm (FIG. 4) on lowering body fat composition and body weight.

FIG. 6. Development of male mice body weight, body fat composition andlean during the study described in Example 2B. The figure shows theeffect of the silica particles with an average pore size of about 3 nm(FIG. 4) on lowering body fat composition and body weight.

FIGS. 7 and 8, Example 2C. The example is included to show that amaterial with structural properties typical for a Silica 5-type (Table2) material has a weaker effect than a typical Silica 2 (Table 2)material on lowering body fat composition and body weight.

FIG. 7. Scanning electron microscopy image (FIG. 7A) and pore sizedistribution (FIG. 7B) of a mesoporous silica material included in thepresent invention.

FIG. 8. Development of male mice body weight, body fat composition andlean during the study described in Example 2B. The figure shows theeffect of the silica particles with an average pore size of about 3 nm(FIG. 4) on lowering body fat composition and body weight.

FIG. 9. Food intake and silica concentration in blood (measured byinductively coupled plasma technique) of mice included in Example 2A and2B.

FIG. 10. Lipid (Cholesterol, HDL and tryglicerides) and glucose levelsin blood from female mice receiving Particle 2 material (representativeof Silica 2 as described in Table 2) in the diet, compared to controlmice not receiving mesoporous silica in the diet.

FIG. 11. Lipid (Cholesterol, HDL and tryglicerides) and glucose levelsin blood from female mice receiving Particle 1 material (representativeof Silica 1 as described in Table 2) in the diet, compared to controlmice not receiving mesoporous silica in the diet.

FIG. 12. Lipid (Cholesterol, HDL and tryglicerides) levels in blood frommale mice receiving Particle 1, Particle 2 and Particle 3 in the diet(representative of respectively Silica 1, 2 and 3 as described in Table2), compared to control mice not receiving mesoporous silica in thediet.

FIG. 13. Example of a Bimodal Pore Mesoporous material with macropores(which is representative for Silica 5 described in Table 2).

EXAMPLES Example 1: Examples of Textural Properties of Porous SilicaMaterials that May be Suitable for the Present Invention

The textural properties of materials that may be suitable for thepresent invention were determined and are included in Table 2.

The pore structure.

The pore structure was determined based on diffraction patterns recordedutilizing low-angle X-ray powder diffraction using CuKa radiation(λ=1.5418 Å at 45 kV and 40 mA) and/or transmission electron microscopy(TEM) with a TEM microscope operating at 300 kV (Cs 0.6 mm, resolution1.7).

BET (Brunauer-Emmett-Teller) Surface Area

The BET surface area, pore volume and pore size distribution (PSD) isdetermined by nitrogen adsorption technique. Nitrogenadsorption/desorption isotherms were measured at liquid nitrogentemperature (−196° C.) using a Micromeritics ASAP2020 volumetricadsorption analyzer for mesoporosity determination. The material sampleswere outgassed before the measurement. The BET equation was used tocalculate the surface area from adsorption data obtained in the relativepressure (p/p°) range of 0.05 and 0.3. The pore volume was calculatedfrom the amount of gas adsorbed at p/p°=0.91. The mesopores pore sizedistribution curves were derived using the density functional theory(DFT) assuming a cylindrical pore model; the pore size and PSD range ofthe mesopores were obtained from those curves according to themethodology described in “Gas Adsorption Equilibria: ExperimentalMethods and Adsorptive Isotherms by Jürgen U. Keller, Springer, 2006”.

The macropores size (defined as pores larger than 50 nm) was determinedusing mercury porosimetry technique and/or by scanning electronmicroscopy (SEM) by measuring the pore width on SEM images recorded withan SEM microscope with no gold coating

TABLE 2 Silica 1 Silica 2 Silica 3 Silica 4 Silica 5 Pore structure2-d-cylindrical 2-d-cylindrical hierarchical hierarchical Worm-likehexagonal hexagonal BET surface 653 709 300 550    685 area (m²/g) Poresize by 2 nm 11 nm 12 nm 12 nm 30 nm DFT mesopores, and mesopores, and 2μm*\ 1.5 μm macropores macropores Pore volume 0.32 1.17  1 0.9 1.6(cm³/g) PSD range 2-3.5 nm 8-13 nm 10-15 nm and, 10-15 nm and, 5-33 nm1-3 μm 1-3 μm

Example 2A: A Large Pore Mesoporous Silica Material (Particle 2 which isRepresentative for Silica 2 Described in Table 2)

Example of the effect of oral administration of mesoporous silicaparticles of about 10 nm pore size (Particle 2) on body weight, body fatcomposition and lean mass as compared to No silica particles (Control)in obese mice.

FIG. 1A shows a scanning electron microscopy (SEM) image of the material(named Particle 2) utilized in the study, which is representative forSilica 2 described in Table 2. The material's pore size distributionmeasured by nitrogen adsorption experiments is shown in FIG. 1Bindicating a sharp pore size distribution in the range of about 8 to 12nm.

Particle 2 material is utilized to exemplify the effect of mesoporoussilicas on body weight and body fat composition (adipose tissue) whenadministered orally in a well-known obesity murine model.

From week 0 to 7.5 the animals were high fat fed in order to make themobese; from week 7.5 to 12 silica particles (Particle 2) were added intothe high fat diet; from week 12 to 20 the animals received standard dietad libitum with two extra high fat meals per week containing silicaparticles.

FIGS. 2 A, C and E show the development of body weight, body fatcomposition and lean respectively during the 20-week long study forfemale animals.

FIGS. 2 B, D and F shows only the data from the last eight weeks of theexperiment. The stars indicate statistically significant differencesbetween mice receiving particles in the diet compared to control micenot receiving particles in the diet.

FIG. 3 shows the same as FIG. 2 for a study with the same experimentalset-up, but performed on males.

Both body fat composition and body weight decrease is observed in theanimal groups receiving mesoporous silica in the diet, as compared tothe control group not receiving porous silica, in both female and malemice (FIGS. 2 and 3 respectively).

A mesoporous material with pore sizes in the order above 10 nm, wasutilized to exemplify the positive weight and cholesterol loweringproperties of a porous silica. The effect of silica mesoporous particleswith large pores, above 10 nm intake on blood lipid levels in obeseblack 6 mice (C57BL/6J) with elevated lipid/cholesterol blood levels andhealthy animals is analyzed. Particles are embedded in the food pelletsand given to the animals during a period of time of about 12 weeks.Blood levels of cholesterol, high-density lipoprotein cholesterol,low-density lipoprotein cholesterol and triglycerides are analyzedduring the 12 weeks of particle intake. Levels of silica in blood aremeasured at the end of the experiment.

Example 2B: A Small Pore Mesoporous Silica Material (Particle 1 which isRepresentative for Silica 1 Described in Table 2)

Another study was performed as described in Example 2A, but utilizing amesoporous silica material with a pore width of about 3 nm (Particle 1)instead of the material named Particle 2. FIG. 4A shows the SEM image ofParticle 1 which is representative for Silica 1 described in Table 2.The material's pore size distribution measured by nitrogen adsorptionexperiments is shown in FIG. 4B, indicating a narrow distribution in therange of about 2.5 to 3.7 nm. FIGS. 5 and 6 show the development of bodyweight, body fat composition and lean in this study. FIGS. 5 and 6 areequivalent to FIGS. 2 and 3 as described in Example 2A, respectively.

No differences in body fat composition or body weight are observed inthe female obese mice receiving silica particles in the diet compared tothe control (FIG. 5).

Both body fat composition and body weight show a tendency to decrease inthe group receiving porous silica in the diet compared to the controlgroup not receiving porous silica in the experiment utilizing male mice(FIG. 6).

A mesoporous material with pore sizes in the order above 3 nm wasutilized to exemplify the positive weight and cholesterol loweringproperties of a porous silica. The effect of silica mesoporous particleswith large pores, above 10 nm intake on blood lipid levels in obeseblack 6 mice (C57BL/6J) with elevated lipid/cholesterol blood levels andhealthy animals is analyzed. Particles are embedded in the food pelletsand given to the animals during a period of time of about 12 weeks.Blood levels of cholesterol, high-density lipoprotein cholesterol,low-density lipoprotein cholesterol and triglycerides are analyzedduring the 12 weeks of particle intake. Levels of silica in blood aremeasured at the end of the experiment. Example 2C: A larger poremesoporous silica material (Particle 3 which is representative forSilica 5 described in Table 2) Another study was performed as describedin Example 2A, but utilizing a mesoporous silica material with a porewidth of about 25 nm (Particle 3) instead of the material named Particle2. FIG. 7A shows the SEM image of the material utilized in this study,Particle 3. The material's pore size distribution measured by nitrogenadsorption is shown in FIG. 7B indicating the distribution to be in therange of about 10 to 35 nm.

Both body fat composition and body weight show a tendency to decrease inthe group receiving porous silica in the diet compared to the controlgroup not receiving porous silica (FIG. 8).

Example 3: Food Intake and Adsorbed Silica for Particle 1 and Particle 2

The food intake of mice included in Example 2A and 2B was measured. Thedaily food intake is the same for mice receiving particles in the dietas in the control animals not receiving silica particles in the diet(FIGS. 9 A and C for Particle 1 and Particle 2 respectively).

The silica concentration in blood was measured by inductively coupledplasma technique at the end of the studies (after about 12 weeks ofsilica particle administration in the diet). No differences in bloodsilica content are observed between mice receiving porous silica in thediet and control mice not receiving porous silica in the diet afterabout 12 weeks of oral administration (FIGS. 9 B and D for Particle 1and Particle 2 respectively).

Example 4: Cholesterol, HDL, P Glucose and Triglyceride Levels in Bloodfor Particle 1, Particle 2 and Particle 3

The Cholesterol, HDL, Glucose and Triglyceride levels in blood wereanalyzed at the end of the studies described in examples 2A, 2B and 2C.

No differences in blood lipid or glucose levels are observed betweenfemale mice receiving Particle 2 or Particle 1 in the diet, compared tocontrol mice not receiving mesoporous silica in the diet after about 12weeks of oral administration (respectively FIG. 10 and FIG. 11). Similarresults are obtained for male mice, where no differences in blood lipidlevels are observed between mice receiving Particle 1, Particle 2 orParticle 3 in the diet, compared to the control mice not receivingmesoporous silica in the diet after about 12 weeks of oraladministration (FIG. 12).

Example 5: Example of a Bimodal Pore Mesoporous Material with Macropores(which is Representative for Silica 5 Described in Table 2)

FIG. 13A shows an SEM image of a material representative for Silica 5 asdescribed in Table 2.

FIG. 13B shows a transmission electron microscopy (TEM) image of thesame material. A more detailed description of the material is summarizedin the table in FIG. 13 C.

1-18. (canceled)
 19. A method of the prophylaxis or treatment of:metabolic syndrome, type 2 diabetes, insulin resistance, orhyperglycemia in a human or animal in need thereof, comprisingadministering to the human or animal an effective amount of a poroussilica material having pores in the mesoscale range of 2-50 nm, whereinthe average pore size of the pores in the mesoscale range is in therange of 2 to 25 nm, and the pore size distribution (PSD) in themesoscale range is such that at least 80% of the pores fall within therange of 2 to 25 nm.
 20. A method of lowering glucose levels in theblood in a human or animal in need thereof, comprising administering tothe human or animal an effective amount of a porous silica materialhaving pores in the mesoscale range of 2-50 nm, wherein the average poresize of the pores in the mesoscale range is in the range of 2 to 25 nm,and the pore size distribution (PSD) in the mesoscale range is such thatat least 80% of the pores fall within the range of 2 to 25 nm.
 21. Themethod of claim 19, wherein the porous silica material is the soleactive ingredient being administered to the human or animal for theprophylaxis or treatment of: metabolic syndrome, type 2 diabetes,insulin resistance or hyperglycemia.
 22. The method of claim 19, whereinthe prophylaxis or treatment of: metabolic syndrome, type 2 diabetes,insulin resistance, or hyperglycemia in a human or animal is achieved byreduction of adipose tissue in the human or animal.
 23. The method ofclaim 19, wherein the porous silica material is orally administered. 24.The method of claim 19, wherein the human or animal is obese.
 25. Themethod of claim 19, wherein the average pore size is in the range of 7to 15 nm.
 26. The method of claim 19, wherein the average pore size isin the range of 10 to 12 nm.
 27. The method of claim 19, wherein the BET(Brunauer-Emmett-Teller theory) surface area is between 300 and 1300m²/g
 28. The method of claim 27, wherein the BET surface area is between500 and 900 m²/g.
 29. The method of claim 19, wherein the pore volumemeasured by nitrogen adsorption is in the range of 0.3 to 1.7 cm³/g. 30.The method of claim 19, wherein the porous silica material additionallyhas a hierarchical porous structure containing both pores in the rangeof 2 to 50 nm and pores larger than 50 nm.
 31. The method of claim 19,wherein the porous silica material has a minimum particle sizedistribution of 300 nm.
 32. The method of claim 20, wherein, wherein theporous silica material is the sole active ingredient being administeredto the human or animal for lowering glucose levels in the blood.
 33. Themethod of claim 20, wherein the lowering glucose levels in the blood ina human or animal is achieved by reduction of adipose tissue in thehuman or animal.
 34. The method of claim 20, wherein the porous silicamaterial is orally administered.
 35. The method of claim 20, wherein thehuman or animal is obese.
 36. The method of claim 20, wherein theaverage pore size is in the range of 7 to 15 nm.
 37. The method of claim20, wherein the average pore size is in the range of 10 to 12 nm. 38.The method of claim 20, wherein the BET (Brunauer-Emmett-Teller theory)surface area is between 300 and 1300 m²/g.
 39. The method of claim 38,wherein the BET surface area is between 500 and 900 m²/g.
 40. The methodof claim 20, wherein the pore volume measured by nitrogen adsorption isin the range of 0.3 to 1.7 cm³/g.
 41. The method of claim 20, whereinthe porous silica material additionally has a hierarchical porousstructure containing both pores in the range of 2 to 50 nm and poreslarger than 50 nm.
 42. The method of claim 20, wherein the porous silicamaterial has a minimum particle size distribution of 300 nm.